DULoxetine (Lexi-Drugs)

ALERT: US Boxed Warning
  Suicidal thoughts and behavior:
Pronunciation

(doo LOX e teen)

Brand Names: US

Cymbalta; Irenka [DSC]

Brand Names: Canada

AG-Duloxetine; APO-Duloxetine; Auro-Duloxetine; Cymbalta; JAMP-Duloxetine; M-Duloxetine; Mar-Duloxetine; MINT-Duloxetine; MYLAN-Duloxetine [DSC]; PMS-Duloxetine; RAN-Duloxetine; RIVA-Duloxetine; SANDOZ Duloxetine

Dosing: Adult

Chemotherapy-induced peripheral neuropathy (off-label use): Oral: Initial: 30 mg once daily for 1 week, then 60 mg once daily (Smith 2013)

Fibromyalgia: Oral: Initial: 30 mg once daily for 1 week, then increase to 60 mg once daily as tolerated. Alternatively, slower titrations have been evaluated: 20 mg once daily, then increase by 20 mg every week up to 60 mg once daily as tolerated (Murakami 2017). Maximum dose: 60 mg/day; doses up to 120 mg/day were studied in clinical trials but did not confer any additional benefit.

Generalized anxiety disorder: Oral: Initial: 60 mg once daily; for some patients, it may be desirable to start at 30 mg once daily for 1 week before increasing to 60 mg once daily. Maintenance: 60 mg once daily. Although doses >60 mg/day did not confer additional benefit in clinical trials, some experts consider it reasonable to escalate the dose in individuals who do not respond satisfactorily to 60 mg/day (Bystritsky 2018; Simon 2010). If dose is escalated, increase by 30 mg increments at intervals of ≥1 week as needed and tolerated (Bystritsky 2018). Maximum: 120 mg/day.

Major depressive disorder (unipolar): Oral: Initial: 40 to 60 mg/day divided twice daily or given as a single daily dose. For some patients, it may be desirable to start at 30 mg once daily for 1 week before increasing to 60 mg once daily. Maintenance: 60 mg once daily. Although doses >60 mg/day did not confer additional benefit in clinical trials, based upon limited data, individual patients may benefit from dose escalation (Nelson 2018; Shelton 2007). If dose is escalated, increase by 30 mg increments at intervals of ≥1 week as needed and tolerated (Nelson 2018). Maximum: 120 mg/day.

Musculoskeletal pain, chronic:

Low back pain, chronic (alternative agent): Note: Adjunct for patients with an inadequate response to nonpharmacologic and NSAID therapy (ACP [Qaseem 2017]; Chou 2018).

Oral: Initial: 30 mg once daily for 1 week, then increase to 60 mg once daily as tolerated; maximum dose: 60 mg/day

Osteoarthritis of the knee (alternative agent): Note: For patients with moderate to severe symptoms and an inadequate response to nonpharmacologic interventions and oral NSAIDs or oral NSAIDs are contraindicated (Deveza 2018; OARSI [McAlindon 2014]).

Oral: Initial: 30 mg once daily for 1 week, then 60 mg once daily. Maximum dose (manufacturer’s labeling): 60 mg/day. Doses up to 120 mg/day may provide some additional benefit (Chappell 2009); however, adverse effects may be increased (Micca 2013).

Neuropathic pain associated with diabetes mellitus: Oral: Initial: 60 mg once daily; lower initial doses may be considered in patients when tolerability is a concern; maximum dose: 60 mg/day; doses up to 120 mg/day were studied in clinical trials but did not confer any additional benefit (Ormseth 2011).

Stress urinary incontinence (women and men) (off-label use): Note: For patients who are unresponsive to nonpharmacologic interventions or have comorbid depression (ACP [Qaseem 2014]; EAU [Burkhard 2018]; NICE 2013).

Oral: 40 mg twice daily (Filocamo 2007; Li 2013). Lower initial doses have been used in women to reduce adverse effects: 20 mg twice daily for 2 weeks then 40 mg twice daily (Castro-Diaz 2007; Schagen van Leeuwen 2008).

Discontinuation of therapy: When discontinuing antidepressant treatment that has lasted for >3 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (APA 2010; WFSBP [Bauer 2015]). Reasons for a slower titration (eg, over 4 weeks) include use of a drug with a half-life <24 hours (eg, paroxetine, venlafaxine), prior history of antidepressant withdrawal symptoms, or high doses of antidepressants (APA 2010; Hirsch 2019). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Shelton 2001). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (WFSBP [Bauer 2015]). Evidence supporting ideal taper rates is limited (Shelton 2001; WFSBP [Bauer 2015]).

Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches, but is contraindicated when switching to or from an MAOI. A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between two SSRIs), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, and pharmacodynamics), and the degree of symptom control desired (Hirsch 2018; Ogle 2013; WFSBP [Bauer 2013]).

Switching to or from an MAOI:

Allow 14 days to elapse between discontinuing an MAOI and initiation of duloxetine.

Allow ≥5 days to elapse between discontinuing duloxetine and initiation of an MAOI according to manufacturer labeling; however, some experts recommend a 14-day washout period (APA 2010).

Dosing: Geriatric

Generalized anxiety disorder: Oral: Initial: 30 mg once daily; after 2 weeks, may increase to 60 mg once daily; titrate doses >60 mg once daily in increments of 30 mg once daily; maximum dose: 120 mg/day.

Major depressive disorder (unipolar): Based on pharmacokinetic studies, manufacturer labeling suggests dosage adjustment is not necessary; however, lower initial starting doses (eg, 20 mg/day) and lower maintenance doses (eg, 30 to 60 mg/day) have been recommended by some experts for elderly patients with comorbid conditions (Kennedy 2005). Refer to adult dosing.

Other indications: Refer to adult dosing.

Discontinuation of therapy: Refer to adult dosing.

Switching antidepressants: Refer to adult dosing.

Dosing: Renal Impairment: Adult

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; however, pharmacokinetic studies suggest that mild to moderate renal impairment (CrCl 30 to 80 mL/minute) has no significant effect on duloxetine clearance.

CrCl <30 mL/minute: Avoid use.

End-stage renal disease (ESRD): Avoid use.

Dosing: Hepatic Impairment: Adult

Avoid use in hepatic impairment.

Dosing: Pediatric

Generalized anxiety disorder: Children and Adolescents 7 to 17 years: Oral: Initial: 30 mg once daily; after 2 weeks, may increase based on response and tolerability to 60 mg once daily; titrate doses >60 mg once daily in increments of 30 mg once daily; maximum dose: 120 mg once daily.

Discontinuation of therapy: Refer to adult dosing.

Switching antidepressants: Refer to adult dosing.

Dosing: Renal Impairment: Pediatric

Children ≥7 years and Adolescents:

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; however, pharmacokinetic studies suggest that mild to moderate renal impairment (CrCl 30 to 80 mL/minute) has no significant effect on duloxetine clearance.

CrCl <30 mL/minute: Avoid use.

End-stage renal disease (ESRD): Avoid use.

Dosing: Hepatic Impairment: Pediatric

Children ≥7 years and Adolescents: Avoid use in hepatic impairment.

Use: Labeled Indications

Fibromyalgia: Management of fibromyalgia

Generalized anxiety disorder: Treatment of generalized anxiety disorder (GAD)

Major depressive disorder (unipolar): Treatment of unipolar major depressive disorder (MDD)

Musculoskeletal pain, chronic: Management of chronic musculoskeletal pain including osteoarthritis of the knee and low back pain

Neuropathic pain associated with diabetes mellitus: Management of pain associated with diabetic peripheral neuropathy

Use: Off-Label: Adult

  Chemotherapy-induced peripheral neuropathyLevel of Evidence [B, G]

Data from a randomized, double-blind, placebo-controlled study support the use of duloxetine in the treatment of pain, numbness, and tingling associated with chemotherapy-induced peripheral neuropathy. Subgroup analyses suggest efficacy may be greater for oxaliplatin-induced neuropathy as opposed to paclitaxel-induced neuropathy Ref.

Based on the American Society of Clinical Oncology clinical practice guidelines for the prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers, duloxetine is suggested in the management of chemotherapy-induced peripheral neuropathy.

  Stress urinary incontinence (men)Level of Evidence [B, G]

Data from a single-blind randomized study and 2 small open-label studies support the use of duloxetine in the treatment of stress urinary incontinence postprostatectomy in patients unresponsive to nonpharmacologic interventions Ref.

Based on the European Association of Urology guidelines on assessment and nonsurgical management of urinary incontinence, in men with stress urinary incontinence, duloxetine either alone or combined with conservative treatment is recommended only to hasten recovery of continence postprostatectomy.

  Stress urinary incontinence (women)Level of Evidence [C, G]

American College of Physicians (ACP) guidelines on nonsurgical management of urinary incontinence recommend against pharmacologic therapy in women with stress urinary incontinence and note that although low-quality, placebo-controlled studies of duloxetine demonstrate beneficial effects, these effects have not been confirmed by data from high-quality studies.

National Institute for Health and Care Excellence (NICE) evidence-based guidelines on the management of urinary incontinence in women state that duloxetine should not be considered as first-line treatment for women with predominant stress urinary incontinence nor routinely used as second-line treatment for women with stress urinary incontinence. However, duloxetine may be considered as second-line therapy for women who decline surgical treatment or who are not suitable candidates for surgical treatment.

Data from controlled trials of low and high quality, systematic reviews, and meta-analyses are conflicting. Additional trials are necessary to further define the role of duloxetine in the treatment of stress urinary incontinence. Access Full Off-Label Monograph

Level of Evidence Definitions
  Level of Evidence Scale
Clinical Practice Guidelines

Anxiety Disorders:

World Federation of Societies of Biological Psychiatry (WFSBP), “Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders, First Revision,” 2008

Depression:

American Psychiatric Association, Practice Guideline for the Treatment of Patients with Major Depressive Disorder, Third Edition, May 2010

Canadian Network for Mood and Anxiety Treatments (CANMAT), “Clinical Guidelines for the Management of Major Depressive Disorder in Adults,” October 2009

National Collaborating Centre for Mental Health (NCCMH), “Depression: The NICE Guideline on the Treatment and Management of Depression in Adults (Updated Edition).” 2010.

World Federation of Societies of Biological Psychiatry (WFSBP), “Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: Update 2013 on the Acute and Continuation Treatment of Unipolar Depressive Disorders,” 2013.

World Federation of Societies of Biological Psychiatry (WFSBP), “Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 2: Maintenance Treatment of Major Depressive Disorder and Treatment of Chronic Depressive Disorders and Subthreshold Depressions,” 2002.

Diabetic Neuropathy:

American Diabetes Association, “Diabetic Neuropathy: Position Statement by the American Diabetes Association,” 2017

Neurology, “Evidence-Based Guideline: Treatment of Painful Diabetic Neuropathy,” April 2011

Administration: Oral

Swallow capsule whole; do not crush or chew. Although the manufacturer does not recommend opening the capsule to facilitate administration, duloxetine has been found to be stable for up to 2 hours after sprinkling the contents of capsule on applesauce or in apple juice (not chocolate pudding) taking care not to crush the pellets and damage the enteric coating (Wells 2008). Tolerability studies of this administration technique have not been conducted. Adverse effects have been reported to the FDA when patients opened the capsules, however, reports do not detail if pellets were crushed (FDA 2007). Administer without regard to meals.

Administration: Pediatric

Oral: Administer without regard to meals. Swallow capsule whole; do not crush or chew. Although the manufacturer does not recommend opening the capsule to facilitate administration, duloxetine has been found to be stable for up to 2 hours after sprinkling the contents of capsule on applesauce or in apple juice (not chocolate pudding) taking care not to crush the pellets and damage the enteric coating (Wells 2008). Tolerability studies of this administration technique have not been conducted. Adverse effects have been reported to the FDA when patients opened the capsules; however, reports do not detail if pellets were crushed (FDA 2007).

Storage/Stability

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Medication Patient Education with HCAHPS Considerations

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, constipation, diarrhea, dry mouth, loss of strength and energy, weight loss, insomnia, fatigue, lack of appetite, or sweating a lot. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), agitation, panic attacks, mood changes, signs of low sodium (headache, difficulty focusing, memory impairment, confusion, weakness, seizures, or change in balance), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), severe headache, dizziness, passing out, memory impairment, tinnitus, urinary retention, change in amount of urine passed, excessive weight gain or loss, sexual dysfunction, vision changes, decreased libido, eye pain, eye irritation, signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Medication Safety Issues
  Sound-alike/look-alike issues:
  Geriatric Patients: High-Risk Medication:
Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021427s049lbl.pdf#page=32, must be dispensed with this medication.

Contraindications

Use of monoamine oxidase (MAO) inhibitors intended to treat psychiatric disorders (concurrently or within 14 days of discontinuing the MAO inhibitor); initiation of MAO inhibitor intended to treat psychiatric disorders within 5 days of discontinuing duloxetine; initiation of duloxetine in a patient receiving linezolid or intravenous methylene blue.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to duloxetine or any component of the formulation; hepatic impairment; severe renal impairment (eg, CrCl <30 mL/minute) or end-stage renal disease (ESRD); uncontrolled narrow-angle glaucoma; concomitant use with thioridazine or with potent CYP1A2 inhibitors.

Warnings/Precautions

Major psychiatric warnings:

• Suicidal thinking/behavior: [US Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient’s family or caregiver should be instructed to closely observe the patient and communicate condition with health care provider. A medication guide concerning the use of antidepressants in children and teenagers should be dispensed with each prescription.

• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.

• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient’s family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their health care provider if any of these symptoms or worsening depression occurs.

Concerns related to adverse effects:

• Bleeding risk: May impair platelet aggregation resulting in increased risk of bleeding events, particularly if used concomitantly with aspirin or NSAIDs due to ulcerogenic potential. Bleeding related to SNRI use has been reported to range from relatively minor bruising and epistaxis to life-threatening hemorrhage.

• CNS depression: Has a low potential to impair cognitive or motor performance; caution operating hazardous machinery or driving.

• Dermatologic: Severe skin reactions (including Stevens-Johnson syndrome and erythema multiforme) have been reported; discontinue immediately if blisters, peeling rash, mucosal erosions, or any other signs of hypersensitivity reactions are suspected.

• Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda 2013; Rizzoli 2012).

• Hepatotoxicity: Avoid use in patients with substantial ethanol intake, evidence of liver disease or hepatic impairment. Rare cases of hepatic failure (including fatalities) have been reported with use. Hepatitis with abdominal pain, hepatomegaly, elevated transaminase levels >20 times the upper limit of normal (ULN) with and without jaundice have all been observed. Discontinue therapy with the presentation of jaundice or other signs of hepatic dysfunction and do not reinitiate therapy unless another source or cause is identified.

• Hyperglycemia: Modest increases in serum glucose and hemoglobin A1c (HbA1c) levels have been observed in some diabetic patients receiving duloxetine for diabetic peripheral neuropathic pain (DPNP).

• Ocular effects: May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.

• Orthostatic hypotension/syncope: May cause orthostatic hypotension/syncope, especially within the first week of therapy and after dose increases. Carefully monitor blood pressure with initiation of therapy, dose increases (especially in patients receiving >60 mg/day), or when using concomitant vasodilators or CYP1A2 inhibitors. Consider dose reduction or discontinuation of duloxetine if orthostatic hypotension or syncope occurs.

• Serotonin syndrome (SS) reactions: Potentially life-threatening serotonin syndrome (SS) has occurred with serotonergic agents (eg, SSRIs, SNRIs), particularly when used in combination with other serotonergic agents (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St John’s wort) or drugs that impair serotonin metabolism (eg, MAO inhibitors, specifically linezolid, methylene blue, and others used for psychiatric disorders). Monitor patients closely for signs/symptoms of SS which may include mental status changes (eg, agitation, hallucinations, delirium), seizures, autonomic instability (eg, tachycardia, dizziness, diaphoresis), neuromuscular symptoms (eg, tremor, rigidity, myoclonus), or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). Discontinue treatment (and any concomitant serotonergic agents) immediately if signs/symptoms arise.

• Sexual dysfunction: May cause or exacerbate sexual dysfunction.

• SIADH and hyponatremia: SSRIs and SNRIs have been associated with the development of SIADH; hyponatremia has been reported rarely (including severe cases with serum sodium <110 mmol/L), predominately in the elderly. Volume depletion and/or concurrent use of diuretics likely increases risk.

• Urinary hesitancy: May cause increased urinary resistance; advise patient to report symptoms of urinary hesitation/difficulty.

Disease-related concerns:

• Gastroparesis: Use caution in patients with impaired gastric motility (eg, some diabetics); may affect stability of the capsule’s enteric coating.

• Hepatic impairment: Avoid use in patients with chronic liver disease or cirrhosis.

• Hypertension: Use caution in patients with hypertension. Although no statistically significant differences in the frequency of sustained elevations of blood pressure were observed in clinical trials when compared with placebo, modest increases in blood pressure have been reported with use. Additionally, rare cases of hypertensive crisis have been reported; blood pressure should be evaluated prior to initiating therapy and periodically thereafter; consider dose reduction or gradual discontinuation of therapy in individuals with sustained hypertension during therapy.

• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. Duloxetine is not FDA approved for the treatment of bipolar depression.

• Renal impairment: Use with caution; clearance is decreased and plasma concentrations are increased; avoid use in patients with CrCl <30 mL/minute or ESRD.

• Seizure disorders: Use caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage or alcoholism (Montgomery 2005).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Fall risk: Falls with serious consequences including bone fractures and hospitalization have been reported in patients receiving therapeutic doses of duloxetine. The risk of falling appears related to the degree of orthostatic decrease in blood pressure. Risks may also be greater in elderly patients, patients taking concomitant medications that induce orthostatic hypotension or are potent CYP1A2 inhibitors, and in patients taking doses >60 mg/day. Consider dose reduction or discontinuation of duloxetine if falls occur.

• Sucrose intolerance: Some formulations may contain sucrose; patients with fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should avoid use.

Other warnings/precautions:

• Discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, lightheadedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010; Fava 2006; Haddad 2001; Shelton 2001; Warner 2006).

Geriatric Considerations

In an 8-week study of elderly patients with a history of recurrent major depressive disorder, improvements in verbal learning and memory, and depression response and remission rates were significantly greater in subjects randomized to duloxetine 60 mg per day compared to placebo. Duloxetine was well tolerated by older patients in clinical trials who accounted for nearly one-third of subjects. Response rate did not differ between younger and older subjects. No dose adjustment is necessary for age alone; adjust dose for renal function. Higher doses are generally required for treatment of general anxiety disorder, neuropathic pain and stress urinary incontinence (off-label use).

A systematic review and meta-analysis of antidepressant placebo-controlled trials in persons with depression and dementia found evidence “suggestive” of efficacy but not of sufficient strength to “confirm” efficacy (Nelson 2011). Older patients with depression being treated with an antidepressant should be closely monitored for response and adverse effects.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Nonteratogenic effects in the newborn following SSRI/SNRI exposure late in the third trimester include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hyper- or hypotonia, hyper-reflexia, jitteriness, irritability, constant crying, and tremor. Symptoms may be due to the toxicity of the SNRIs/SSRIs or a discontinuation syndrome and may be consistent with serotonin syndrome associated with SSRI treatment. The long-term effects of in utero SNRI/SSRI exposure on infant development and behavior are not known.

The ACOG recommends that therapy with SSRIs or SNRIs during pregnancy be individualized; treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. According to the American Psychiatric Association (APA), the risks of medication treatment should be weighed against other treatment options and untreated depression. For women who discontinue antidepressant medications during pregnancy and who may be at high risk for postpartum depression, the medications can be restarted following delivery. Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy.

Health care providers are encouraged to enroll women exposed to duloxetine during pregnancy in the Cymbalta Pregnancy Registry (866-814-6975 or http://cymbaltapregnancyregistry.com).

Pregnant women exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Women 18 to 45 years of age or their health care providers may contact the registry by calling 844-405-6185. Enrollment should be done as early in pregnancy as possible.

Breast-Feeding Considerations

Duloxetine is present in breast milk.

The relative infant dose (RID) of duloxetine is 2.3% when calculated using the highest breast milk concentration located and compared to a weight-adjusted maternal dose of 60 mg/day.

In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000). However, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Larsen 2015).

The RID of duloxetine was calculated using a milk concentration of ~120 mcg/L, providing an estimated daily infant dose via breast milk of 0.02 mg/kg/day. This milk concentration was obtained following maternal administration of duloxetine 60 mg/day (Briggs 2009). Duloxetine has also been detected in the serum of a breastfeeding infant (Boyce 2011).

Information related to the use of duloxetine in breastfeeding women is limited. Infants of mothers using psychotropic medications should be monitored daily for changes in sleep, feeding patterns, and behavior (Bauer 2013) as well as infant growth and neurodevelopment (Sachs 2013; Sriraman 2015).

The manufacturer recommends that caution be exercised when administering duloxetine to breastfeeding women. When first initiating an antidepressant in a breastfeeding woman, agents other than duloxetine are preferred. Women successfully treated with duloxetine during pregnancy may continue use while breastfeeding if there are no other contraindications (Berle 2011).

Lexicomp Pregnancy & Lactation, In-Depth
Briggs’ Drugs in Pregnancy & Lactation
Adverse Reactions

>10%:

Central nervous system: Headache (13% to 14%), drowsiness (9% to 11%; dose related), fatigue (7% to 11%; dose related)

Gastrointestinal: Nausea (18% to 23%), xerostomia (adults: 11% to 14%; dose related, children and adolescents: 2%), abdominal pain (children and adolescents: 13%, adults: 5%)

Endocrine & metabolic: Weight loss (children and adolescents: 14%, adults: ≥1%)

Neuromuscular & skeletal: Weakness (≤7% to ≤11%; dose related)

1% to 10%:

Cardiovascular: Flushing (3%), increased blood pressure (2%), palpitations (≥1% to 2%)

Central nervous system: Insomnia (7% to 10%; dose related), dizziness (8% to 9%), agitation (3% to 4%), anxiety (3%), delayed ejaculation (2%; dose related), yawning (≥1% to 2%), abnormal dreams (≥1%), anorgasmia (≥1%), chills (≥1%), hypoesthesia (≥1%), lethargy (≥1%), paresthesia (≥1%), rigors (≥1%), sleep disorder (≥1%), vertigo (≥1%)

Dermatologic: Diaphoresis (6%), pruritus (≥1%)

Endocrine & metabolic: Decreased libido (3%), orgasm abnormal (≥1% to 2%), hot flash (≥1%), weight gain (≥1%)

Gastrointestinal: Constipation (9% to 10%; dose related), decreased appetite (6% to 10%; dose related), vomiting (children and adolescents: 9%; adults: 3% to 4%), diarrhea (6% to 9%), dyspepsia (2%), dysgeusia (≥1%), flatulence (≥1%)

Genitourinary: Erectile dysfunction (4%), ejaculatory disorder (2%), urinary frequency (≥1%)

Hepatic: Increased serum ALT (>3 x ULN: 1%)

Neuromuscular & skeletal: Tremor (2% to 3%; dose related), musculoskeletal pain (≥1%)

Ophthalmic: Blurred vision (≥1% to 3%)

Respiratory: Oropharyngeal pain (children and adolescents: 4%; adults: ≥1%), cough (children and adolescents: 3%)

<1%, postmarketing, and/or case reports: Abnormal gait, acute pancreatitis, aggressive behavior (particularly early in treatment or after treatment discontinuation), akathisia, anaphylaxis, angioedema, angle-closure glaucoma, apathy, bruxism, cardiomyopathy (takotsubo), cholestatic jaundice, cold extremities, confusion, contact dermatitis, dehydration, diplopia, disorientation, disturbance in attention, dry eye syndrome, dysarthria, dyskinesia, dyslipidemia, dysphagia, dysuria, ecchymoses, elevated glycosylated hemoglobin (diabetic neuropathic pain), emotional lability, epistaxis, eructation, erythema, erythema multiforme, extrapyramidal reaction, falling, feeling abnormal, galactorrhea, gastric ulcer, gastritis, gastroenteritis, gastrointestinal hemorrhage, gynecological bleeding, halitosis, hallucination, hematoma, hepatic failure, hepatitis, hepatomegaly, hostility, hyperbilirubinemia, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperlipidemia, hyperprolactinemia, hypersensitivity angiitis, hypersensitivity reaction, hypertensive crisis, hypertonia, hypokalemia, hypomania, hyponatremia, hypothyroidism, impulsivity, increased blood pressure, increased creatine phosphokinase, increased diastolic blood pressure, increased serum alkaline phosphatase, increased serum AST, increased serum bicarbonate, increased serum transaminases, increased thirst, irritability, jaundice, laryngitis, lymphocytic colitis, malaise, malodorous urine, mania, menopausal symptoms, menstrual disease, myocardial infarction, muscle spasm, muscle twitching, myoclonus, night sweats, nocturia, orthostatic hypotension, otalgia, outbursts of anger (particularly early in treatment or after treatment discontinuation), panic attack, petechia, pharyngeal edema, polyuria, restless leg syndrome, seizure, sensation of cold, serotonin syndrome, sexual disorder, SIADH, skin photosensitivity, skin rash, Stevens-Johnson syndrome, stomatitis, suicidal ideation, supraventricular cardiac arrhythmia, syncope, tachycardia, testicular pain, tinnitus, trismus, urinary retention, urinary urgency, urticaria, visual disturbance

Allergy and Idiosyncratic Reactions
Metabolism/Transport Effects

Substrate of CYP1A2 (major), CYP2D6 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2D6 (moderate)

Drug Interactions 

Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Risk C: Monitor therapy

Ajmaline: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Ajmaline. Risk C: Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Specifically, risks of psychomotor impairment may be enhanced. Alcohol (Ethyl) may enhance the hepatotoxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Particularly duloxetine and milnacipran. Management: Patients receiving serotonin/norepinephrine reuptake inhibitors (SNRIs) should be advised to avoid alcohol. Monitor for increased psychomotor impairment and hepatotoxicity in patients who consume alcohol during treatment with SNRIs. Risk D: Consider therapy modification

Alpha-/Beta-Agonists: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the tachycardic effect of Alpha-/Beta-Agonists. Serotonin/Norepinephrine Reuptake Inhibitors may enhance the vasopressor effect of Alpha-/Beta-Agonists. Risk D: Consider therapy modification

Alpha2-Agonists: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the antihypertensive effect of Alpha2-Agonists. Exceptions: Apraclonidine. Risk C: Monitor therapy

Amphetamines: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Amphetamines. Risk C: Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Risk C: Monitor therapy

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Risk C: Monitor therapy

Apixaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Risk C: Monitor therapy

ARIPiprazole: May enhance the adverse/toxic effect of DULoxetine. ARIPiprazole may enhance the serotonergic effect of DULoxetine. This could result in serotonin syndrome. DULoxetine may increase the serum concentration of ARIPiprazole. Risk C: Monitor therapy

Aspirin: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy

Brexpiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: If brexpiprazole is to be used together with both a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor, the brexpiprazole dose should be reduced to 25% of the usual dose. Risk C: Monitor therapy

Broccoli: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

Bromopride: May enhance the adverse/toxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Risk X: Avoid combination

Cannabis: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

CloZAPine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy

Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy

CYP1A2 Inducers (Moderate): May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CYP1A2 Inhibitors (Strong): May increase the serum concentration of DULoxetine. Risk X: Avoid combination

CYP2D6 Inhibitors (Strong): May increase the serum concentration of DULoxetine. Risk C: Monitor therapy

CYP2D6 Substrates (High risk with Inhibitors): CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Exceptions: Tamoxifen.Risk C: Monitor therapy

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

Dabigatran Etexilate: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Risk C: Monitor therapy

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Risk X: Avoid combination

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk C: Monitor therapy

Deferasirox: May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Risk D: Consider therapy modification

Edoxaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Risk C: Monitor therapy

Eliglustat: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Reduce the eliglustat dose to 84 mg daily. Avoid use of eliglustat in combination with a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor. Risk D: Consider therapy modification

Fat Emulsion (Fish Oil Based): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Risk C: Monitor therapy

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Risk D: Consider therapy modification

Ibritumomab Tiuxetan: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Indoramin: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Indoramin. Risk C: Monitor therapy

Inotersen: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Iobenguane Radiopharmaceutical Products: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose. Risk X: Avoid combination

Ioflupane I 123: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the diagnostic effect of Ioflupane I 123. Risk C: Monitor therapy

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Linezolid: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Consider alternatives to this combination whenever possible, and discontinue serotonin/norepinephrine reuptake inhibitors (SNRIs) prior to administration of linezolid. Risk D: Consider therapy modification

Linezolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Due to a risk of serotonin syndrome/serotonin toxicity, discontinue serotonin modulators 2 weeks prior to the administration of linezolid. If urgent initiation of linezolid is needed, discontinue serotonin modulators immediately and monitor closely. Risk D: Consider therapy modification

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Risk C: Monitor therapy

Methylene Blue: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Risk X: Avoid combination

Methylphenidate: May enhance the adverse/toxic effect of Serotonin Modulators. Specifically, the risk of serotonin syndrome or serotonin toxicity may be increased. Risk C: Monitor therapy

Metoclopramide: May enhance the adverse/toxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Management: Seek alternatives to this combination when possible. Monitor patients receiving metoclopramide with serotonin/norepinephrine reuptake inhibitors for signs of extrapyramidal symptoms, neuroleptic malignant syndrome, and serotonin syndrome. Risk D: Consider therapy modification

Metoprolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Metoprolol. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Exceptions: Linezolid; Methylene Blue; Tedizolid. Risk X: Avoid combination

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (Nonselective): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Risk C: Monitor therapy

Obeticholic Acid: May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased.Risk C: Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Opioid Agonists: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Risk C: Monitor therapy

PARoxetine: DULoxetine may enhance the serotonergic effect of PARoxetine. This could result in serotonin syndrome. PARoxetine may increase the serum concentration of DULoxetine. Management: Coadminister with caution. If duloxetine and paroxetine are used in combination, monitor for signs and symptoms of serotonin toxicity/serotonin syndrome, as well as other toxic effects of duloxetine. Risk D: Consider therapy modification

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Perhexiline: CYP2D6 Inhibitors may increase the serum concentration of Perhexiline. Management: Consider alternatives to this combination if possible. If combined, monitor for increased perhexiline serum concentrations and toxicities (eg, hypoglycemia, neuropathy, liver dysfunction). Perhexiline dose reductions will likely be required. Risk D: Consider therapy modification

Propafenone: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Propafenone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Rivaroxaban: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Rivaroxaban. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Risk C: Monitor therapy

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Risk C: Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid.Risk C: Monitor therapy

Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Consider alternatives with less of an inhibitory effect on CYP2D6 activity when possible. Risk D: Consider therapy modification

Tamsulosin: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Tamsulosin. Risk C: Monitor therapy

Tedizolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Risk C: Monitor therapy

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

Thioridazine: CYP2D6 Inhibitors may increase the serum concentration of Thioridazine. Risk X: Avoid combination

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy

Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Tobacco (Smoked): May decrease the serum concentration of DULoxetine. Risk C: Monitor therapy

TraMADol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Risk C: Monitor therapy

TraMADol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Risk C: Monitor therapy

Tricyclic Antidepressants: DULoxetine may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. DULoxetine may decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Risk X: Avoid combination

Vemurafenib: May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs.Risk D: Consider therapy modification

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Monitoring Parameters

Blood pressure should be checked prior to initiating therapy and then regularly monitored, especially in patients with a high baseline blood pressure; mental status for depression, suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, panic attacks or other unusual changes in behavior; glucose levels and HbA1c levels in diabetic patients, creatinine, BUN, transaminases

Advanced Practitioners Physical Assessment/Monitoring

Assess renal function and liver function prior to use; avoid use in severe impairment. Monitor blood pressure (can cause elevation or orthostatic hypotension) at the beginning of treatment and periodically throughout. Monitor for worsening of depression and suicide ideation. Monitor pain levels for response. Taper dosage slowly when discontinuing. Do not discontinue abruptly.

Nursing Physical Assessment/Monitoring

Monitor blood pressure (can cause elevation or orthostatic hypotension) at the beginning of treatment and periodically throughout. Monitor for worsening of pain, depression, and suicide ideation. Taper dosage slowly when discontinuing. Do not discontinue abruptly. Educate patients to report any skin rash or irritation and to avoid alcohol.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule Delayed Release Particles, Oral:

Cymbalta: 20 mg, 30 mg, 60 mg [contains fd&c blue #2 (indigotine)]

Irenka: 40 mg [DSC]

Generic: 20 mg, 30 mg, 40 mg, 60 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule Delayed Release Particles, Oral:

Cymbalta: 30 mg, 60 mg [contains FD&C BLUE #2 (INDIGOTINE)]

Generic: 30 mg, 60 mg

Anatomic Therapeutic Chemical (ATC) Classification
  • N06AX21
Generic Available (US)

Yes

Pricing: US

Capsule, enteric pellets (Cymbalta Oral)

20 mg (per each): $8.89

30 mg (per each): $9.97

60 mg (per each): $9.97

Capsule, enteric pellets (DULoxetine HCl Oral)

20 mg (per each): $1.80 – $7.00

30 mg (per each): $1.92 – $7.85

40 mg (per each): $7.85

60 mg (per each): $1.92 – $7.85

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer’s AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a weak inhibitor of dopamine reuptake. Duloxetine has no significant activity for muscarinic cholinergic, H1-histaminergic, or alpha2-adrenergic receptors. Duloxetine does not possess MAO-inhibitory activity.

Pharmacodynamics/Kinetics

Absorption: Well absorbed, 2-hour delay in absorption after ingestion; food decreases extent of absorption ~10% (no effect on Cmax)

Distribution: ~1,640 L

Protein binding: >90%; primarily to albumin and alpha1-acid glycoprotein

Metabolism: Hepatic, via CYP1A2 and CYP2D6; forms multiple metabolites (inactive)

Half-life elimination: ~12 hours (range: 8 to 17 hours); ~4 hours longer in elderly women

Time to peak: 6 hours; 10 hours when ingested with food

Excretion: Urine (~70%; <1% of total dose as unchanged drug); feces (~20%)

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: Cmax and AUC were ~100% greater in patients with ESRD receiving intermittent hemodialysis.

Hepatic function impairment: Metabolism and elimination of duloxetine were decreased in patients with clinically evident hepatic impairment.

Geriatric: AUC was ~25% higher in elderly women.

Cigarette smoking: Duloxetine bioavailability is reduced by ~33% in smokers.

Local Anesthetic/Vasoconstrictor Precautions

Although duloxetine is not a tricyclic antidepressant, it does block norepinephrine reuptake within the CNS synapses as part of its mechanism. It has been suggested that vasoconstrictors be administered with caution and to monitor vital signs in dental patients taking antidepressants that affect norepinephrine in this way.

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation). See Effects on Bleeding.

Effects on Bleeding

Platelet dysfunction (ie, impaired platelet aggregation) may occur during treatment with serotonin norepinephrine reuptake inhibitors (SNRIs) such as duloxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication. Concurrent NSAID use may increase this risk.

Index Terms

(+)-(S)-N-Methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine Hydrochloride; Duloxetine HCl; Duloxetine Hydrochloride; LY248686

FDA Approval Date
August 03, 2004
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Ogle NR, Akkerman SR. Guidance for the discontinuation or switching of antidepressant therapies in adults. J Pharm Pract. 2013;26(4):389-396. doi: 10.1177/0897190012467210.[PubMed 23459282]

Ormseth MJ, Scholz BA, Boomershine CS. Duloxetine in the management of diabetic peripheral neuropathic pain. Patient Prefer Adherence. 2011;5:343-356. doi: 10.2147/PPA.S16358.[PubMed 21845034]

Qaseem A, Dallas P, Forciea MA, Starkey M, Denberg TD, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Nonsurgical management of urinary incontinence in women: a clinical practice guideline from the American College of Physicians [published correction appears in Ann Intern Med. 2014;161(10):764]. Ann Intern Med. 2014;161(6):429-440. doi: 10.7326/M13-2410.[PubMed 25222388]

Qaseem A, Wilt TJ, McLean RM, Forciea MA; Clinical Guidelines Committee of the American College of Physicians. Noninvasive treatments for acute, subacute, and chronic low back pain: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2017;166(7):514-530. doi: 10.7326/M16-2367.[PubMed 28192789]

Rabenda V, Nicolet D, Beaudart C, et al. Relationship between use of antidepressants and risk of fractures: a meta-analysis. Osteoporos Int. 2013;24(1):121-137.[PubMed 22638709]

Rizzoli R, Cooper C, Reginster JY, et al. Antidepressant medications and osteoporosis. Bone. 2012;51(3):606-613.[PubMed 22659406]

Sachs HC; Committee on Drugs. The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Pediatrics. 2013;132(3):e796-809.[PubMed 23979084]

Schagen van Leeuwen JH, Lange RR, Jonasson AF, Chen WJ, Viktrup L. Efficacy and safety of duloxetine in elderly women with stress urinary incontinence or stress-predominant mixed urinary incontinence. Maturitas. 2008;60(2):138-147.[PubMed 18547757]

Schlenker B, Gratzke C, Reich O, Schorsch I, Seitz M, Stief CG. Preliminary results on the off-label use of duloxetine for the treatment of stress incontinence after radical prostatectomy or cystectomy. Eur Urol. 2006;49(6):1075-1078.[PubMed 16481094]

Shelton RC. Steps following attainment of remission: discontinuation of antidepressant therapy. Prim Care Companion J Clin Psychiatry. 2001;3(4):168-174.[PubMed 15014601]

Shelton RC, Andorn AC, Mallinckrodt CH, et al. Evidence for the efficacy of duloxetine in treating mild, moderate, and severe depression. Int Clin Psychopharmacol. 2007;22(6):348-355.[PubMed 17917553]

Simon NM, Worthington JJ, Moshier SJ, et al. Duloxetine for the treatment of generalized social anxiety disorder: a preliminary randomized trial of increased dose to optimize response. CNS Spectr. 2010;15(7):367-373.[PubMed 20625362]

Smith EM, Pang H, Cirrincione C, et al; Alliance for Clinical Trials in Oncology. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013;309(13):1359-67. doi: 10.1001/jama.2013.2813.[PubMed 23549581]

Sriraman NK, Melvin K, Meltzer-Brody S. ABM Clinical Protocol #18: Use of antidepressants in breastfeeding mothers. Breastfeed Med. 2015;10(6):290-299.[PubMed 26204124]

Warner CH, Bobo W, Warner C, Reid S, Rachal J. Antidepressant discontinuation syndrome. Am Fam Physician. 2006;74:449-456.[PubMed 16913164]

Wells KA and Losin WG, “In vitro Stability, Potency, and Dissolution of Duloxetine Enteric-Coated Pellets After Exposure to Applesauce, Apple Juice, and Chocolate Pudding,” Clin Ther, 2008, 30(7):1300-8.[PubMed 18691989]

Brand Names: International

Alacir (CR, DO, GT, HN, NI, PA, SV, UY); Ambidext (LK); Andepra (AU); Ariclaim (AT, BE, BG, CH, CZ, DE, DK, EE, ES, FI, FR, GB, GR, IE, IT, MT, NL, NO, PL, PT, RO, RU, SE, SK, TR); Aritavi (CZ, IE); Cicleno (CL); Cimal (CO); Clonia (CR, DO, GT, HN, NI, PA, SV); Cymbalta (AE, AR, AT, AU, BB, BE, BG, BH, BR, CH, CL, CN, CO, CR, CY, CZ, DE, DK, DO, EC, EE, EG, ES, FI, FR, GB, GT, HK, HN, HR, HU, ID, IE, IL, IT, JO, JP, KR, KW, LB, LT, LU, LV, MT, MX, MY, NI, NL, NO, NZ, PA, PE, PH, PL, QA, RO, RU, SA, SE, SG, SK, TH, TR, TW); Cymbatex (EG); Dalaful (CR, DO, GT, HN, NI, PA, SV); Delok (IN); Deloxi (BD); Deuloks (ZW); Doxet (PE); Dulan (LK); Dulonorm (LB); Dulopressive (EG); Duloprex (KR); Dulox (BD); Duloxa (KR, LB); Duloxeteg (CR, DO, GT, HN, NI, PA, SV); Dulsevir (LV); Duroceptol (KR); Duseta (KR); Duxela (KR); Duxetin (AR, UY); Duxetine (TW); Duxtin (BD); Inmox (CO); Loxentia (IE); Loxyt (LB); Lyta (LK); Nitidex (AR); Psynil (PH); Sebata (KR); Xeristar (AT, BE, BG, CH, CZ, DE, DK, EE, ES, FI, FR, GB, HR, IE, IT, MT, NL, NO, RO, RU, SE, SK, TR); Xinolax DR (BD); Yentreve (AE, AT, BE, BG, CH, CL, CZ, DE, DK, EE, FI, FR, GB, HR, IE, IL, IT, LU, MT, MX, NL, NO, NZ, PL, RU, SE, SK, TR)

Duloxetine (Patient Education – Adult Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(doo LOX e teen)

Brand Names: US

Cymbalta; Irenka [DSC]

Brand Names: Canada

Cymbalta; Duloxetine DR

Warning
  • Drugs like this one have raised the chance of suicidal thoughts or actions in children and young adults. The risk may be greater in people who have had these thoughts or actions in the past. All people who take this drug need to be watched closely. Call the doctor right away if signs like low mood (depression), nervousness, restlessness, grouchiness, panic attacks, or changes in mood or actions are new or worse. Call the doctor right away if any thoughts or actions of suicide occur.
What is this drug used for?
  • It is used to treat low mood (depression).
  • It is used to treat anxiety.
  • It is used to help painful nerve diseases and diabetic nerve problems.
  • It is used to ease long-term pain problems.
  • Some products are used to treat fibromyalgia. Talk with the doctor.
  • It may be given to you for other reasons. Talk with the doctor.
What do I need to tell my doctor BEFORE I take this drug?
  • If you have an allergy to duloxetine or any other part of this drug.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have any of these health problems: Kidney disease or liver disease.
  • If you are taking thioridazine.
  • If you are taking any of these drugs: Ciprofloxacin or fluvoxamine.
  • If you are taking any of these drugs: Linezolid or methylene blue.
  • If you have taken certain drugs used for low mood (depression) like isocarboxazid, phenelzine, or tranylcypromine or drugs used for Parkinson’s disease like selegiline or rasagiline in the last 14 days. Taking this drug within 14 days of those drugs can cause very bad high blood pressure.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this drug with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.
What are some things I need to know or do while I take this drug?
  • Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists.
  • Avoid driving and doing other tasks or actions that call for you to be alert until you see how this drug affects you.
  • To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
  • Low blood pressure, falls, and passing out have happened with this drug. Falls may lead to problems like broken bones and the need to go to the hospital. The chance of falling is raised with older people. Talk with the doctor.
  • If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
  • Check blood pressure and heart rate as the doctor has told you. Talk with the doctor.
  • Have your eye pressure checked. Talk with your doctor.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Avoid drinking alcohol while taking this drug.
  • Talk with your doctor before you use other drugs and natural products that slow your actions.
  • This drug may raise the chance of bleeding. Sometimes, bleeding can be life-threatening. Talk with the doctor.
  • A very bad and sometimes deadly health problem called serotonin syndrome may happen. The risk may be greater if you take this drug with drugs for depression, migraines, or certain other drugs. Call your doctor right away if you have agitation; change in balance; confusion; hallucinations; fever; fast or abnormal heartbeat; flushing; muscle twitching or stiffness; seizures; shivering or shaking; sweating a lot; very bad diarrhea, upset stomach, or throwing up; or very bad headache.
  • Some people may have a higher chance of eye problems with this drug. Your doctor may want you to have an eye exam to see if you have a higher chance of these eye problems. Call your doctor right away if you have eye pain, change in eyesight, or swelling or redness in or around the eye.
  • This drug may affect certain lab tests. Tell all of your health care providers and lab workers that you take this drug.
  • If you are 65 or older, use this drug with care. You could have more side effects.
  • This drug may affect growth in children and teens in some cases. They may need regular growth checks. Talk with the doctor.
  • Use with care in children. Talk with the doctor.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this drug while you are pregnant.
  • Taking this drug in the third trimester of pregnancy may lead to some health problems in the newborn. Talk with the doctor.
  • Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.
What are some side effects that I need to call my doctor about right away?
  • WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:
  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of low sodium levels like headache, trouble focusing, memory problems, feeling confused, weakness, seizures, or change in balance.
  • Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
  • Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
  • Memory problems or loss.
  • Ringing in ears.
  • Not able to pass urine or change in how much urine is passed.
  • A big weight gain or loss.
  • Sex problems like lowered interest in sex or ejaculation problems.
  • Very bad and sometimes deadly liver problems have happened with this drug. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.
What are some other side effects of this drug?
  • All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:
  • Upset stomach or throwing up.
  • Constipation.
  • Diarrhea.
  • Headache.
  • Dry mouth.
  • Not able to sleep.
  • Feeling sleepy.
  • Not hungry.
  • Sweating a lot.
  • Feeling tired or weak.
  • Dizziness.
  • Weight loss.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best taken?
  • Use this drug as ordered by your doctor. Read all information given to you. Follow all instructions closely.
  • To gain the most benefit, do not miss doses.
  • Keep taking this drug as you have been told by your doctor or other health care provider, even if you feel well.
  • Take with or without food. Take with food if it causes an upset stomach.
  • Swallow whole. Do not chew, break, or crush.
  • Do not open the capsules.
  • Do not stop taking this drug all of a sudden without calling your doctor. You may have a greater risk of side effects. If you need to stop this drug, you will want to slowly stop it as ordered by your doctor.
What do I do if I miss a dose?
  • Take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.
How do I store and/or throw out this drug?
  • Store at room temperature.
  • Protect from light.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
General drug facts
  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else’s drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
Duloxetine (Patient Education – Pediatric Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(doo LOX e teen)

Brand Names: US

Cymbalta; Irenka [DSC]

Brand Names: Canada

Cymbalta; Duloxetine DR

Warning
  • Drugs like this one have raised the chance of suicidal thoughts or actions in children and young adults. The risk may be greater in people who have had these thoughts or actions in the past. All people who take this drug need to be watched closely. Call the doctor right away if signs like low mood (depression), nervousness, restlessness, grouchiness, panic attacks, or changes in mood or actions are new or worse. Call the doctor right away if any thoughts or actions of suicide occur.
What is this drug used for?
  • It is used to treat anxiety.
  • It may be given to your child for other reasons. Talk with the doctor.
What do I need to tell the doctor BEFORE my child takes this drug?
  • If your child has an allergy to this drug or any part of this drug.
  • If your child is allergic to any drugs like this one or any other drugs, foods, or other substances. Tell the doctor about the allergy and what signs your child had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If your child has any of these health problems: Kidney disease or liver disease.
  • If your child is taking thioridazine.
  • If your child is taking any of these drugs: Ciprofloxacin or fluvoxamine.
  • If your child is taking any of these drugs: Linezolid or methylene blue.
  • If your child has taken certain drugs used for low mood (depression) like isocarboxazid, phenelzine, or tranylcypromine or drugs used for certain other health problems in the last 14 days. Taking this drug within 14 days of those drugs can cause very bad high blood pressure.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell the doctor and pharmacist about all of your child’s drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for your child to take this drug with all of his/her drugs and health problems. Do not start, stop, or change the dose of any drug your child takes without checking with the doctor.
What are some things I need to know or do while my child takes this drug?
  • Tell all of your child’s health care providers that your child is taking this drug. This includes your child’s doctors, nurses, pharmacists, and dentists.
  • Have your child avoid tasks or actions that call for alertness until you see how this drug affects your child. These are things like riding a bike, playing sports, or using items such as scissors, lawnmowers, electric scooters, toy cars, or motorized vehicles.
  • To lower the chance of feeling dizzy or passing out, have your child rise slowly if your child has been sitting or lying down. Have your child be careful going up and down stairs.
  • Low blood pressure, falls, and passing out have happened with this drug. Falls may lead to problems like broken bones and the need to go to the hospital. The chance of falling is raised with older people. Talk with the doctor.
  • If your child has high blood sugar (diabetes), you will need to watch his/her blood sugar closely.
  • Check blood pressure and heart rate as the doctor has told you. Talk with the doctor.
  • Have your child’s eye pressure checked. Talk with your child’s doctor.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Alcohol may interact with this drug. Be sure your child does not drink alcohol.
  • Talk with your child’s doctor before giving your child other drugs and natural products that may slow your child’s actions.
  • This drug may raise the chance of bleeding. Sometimes, bleeding can be life-threatening. Talk with the doctor.
  • Some people may have a higher chance of eye problems with this drug. The doctor may want your child to have an eye exam to see if your child has a higher chance of these eye problems. Call the doctor right away if your child has eye pain, change in eyesight, or swelling or redness in or around the eye.
  • This drug may affect certain lab tests. Tell all of your child’s health care providers and lab workers that your child takes this drug.
  • This drug may affect growth in children and teens in some cases. They may need regular growth checks. Talk with the doctor.
  • Use with care in children. Talk with the doctor.
  • If your child is pregnant or breast-feeding a baby:
  • Talk with the doctor if your child is pregnant, becomes pregnant, or is breast-feeding a baby. You will need to talk about the benefits and risks to your child and the baby.
  • Taking this drug in the third trimester of pregnancy may lead to some health problems in the newborn. Talk with the doctor.
What are some side effects that I need to call my child’s doctor about right away?
  • WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your child’s doctor or get medical help right away if your child has any of the following signs or symptoms that may be related to a very bad side effect:
  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of low mood (depression), thoughts of killing yourself, nervousness, emotional ups and downs, thinking that is not normal, anxiety, or lack of interest in life.
  • Signs of low sodium levels like headache, trouble focusing, memory problems, feeling confused, weakness, seizures, or change in balance.
  • Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
  • Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
  • Change in the way your child acts.
  • Very bad dizziness or passing out.
  • Memory problems or loss.
  • Ringing in ears.
  • Seizures.
  • Very bad headache.
  • Feeling very tired or weak.
  • Not able to pass urine or change in how much urine is passed.
  • A big weight gain or loss.
  • A very bad and sometimes deadly health problem called serotonin syndrome may happen. The risk may be greater if your child takes this drug with drugs for depression, migraines, or certain other drugs. Call your child’s doctor right away if your child has agitation; change in balance; confusion; hallucinations; fever; a fast or abnormal heartbeat; flushing; muscle twitching or stiffness; seizures; shivering or shaking; sweating a lot; very bad diarrhea, upset stomach, or throwing up; or very bad headache.
  • Very bad and sometimes deadly liver problems have happened with this drug. Call your child’s doctor right away if your child has signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if your child has signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in the mouth, throat, nose, or eyes.
  • If your child is or may be sexually active:
  • Sex problems like lowered interest in sex or ejaculation problems.
What are some other side effects of this drug?
  • All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your child’s doctor or get medical help if any of these side effects or any other side effects bother your child or do not go away:
  • Feeling nervous and excitable.
  • Upset stomach or throwing up.
  • Constipation.
  • Diarrhea.
  • Headache.
  • Dry mouth.
  • Not able to sleep.
  • Feeling sleepy.
  • Not hungry.
  • Sweating a lot.
  • Feeling tired or weak.
  • Dizziness.
  • Belly pain.
  • Weight loss.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your child’s doctor. Call your child’s doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best given?
  • Give this drug as ordered by your child’s doctor. Read all information given to you. Follow all instructions closely.
  • To gain the most benefit, do not miss giving your child doses.
  • Keep giving this drug to your child as you have been told by your child’s doctor or other health care provider, even if your child feels well.
  • Give this drug with or without food. Give with food if it causes an upset stomach.
  • Have your child swallow whole. Do not let your child chew, break, or crush.
  • Do not open the capsules.
  • Do not stop giving this drug to your child all of a sudden without calling the doctor. Your child may have a greater risk of side effects. If your child needs to stop this drug, you will want to slowly stop it as told by the doctor.
What do I do if my child misses a dose?
  • Give a missed dose as soon as you think about it.
  • If it is close to the time for your child’s next dose, skip the missed dose and go back to your child’s normal time.
  • Do not give 2 doses at the same time or extra doses.
How do I store and/or throw out this drug?
  • Store at room temperature.
  • Protect from light.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
General drug facts
  • If your child’s symptoms or health problems do not get better or if they become worse, call your child’s doctor.
  • Do not share your child’s drug with others and do not give anyone else’s drug to your child.
  • Keep a list of all your child’s drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your child’s doctor.
  • Talk with your child’s doctor before giving your child any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.